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Completed

NCT Number: NCT03763656

Pharmacokinetics of Oral Hydroxyurea Solution

An open label, safety and pharmacokinetic study of oral hydroxyurea solution administered to children from 6 months to 17.99 years (i.e. to the day before 18th birthday), with a 12 to 15 month treatment period for each participant. The study treatment duration will be for 6 months at the maximum tolerated dose [MTD], which is usually reached by 6 months after initiation of treatment. For patients in whom time to MTD is longer than 6 months or not achieved at all, the maximum duration of study treatment will be 15 months.

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Key information

Conditions

Sickle Cell Disease Anemia Anemia, Hemolytic Anemia, Hemolytic, Congenital Anemia, Sickle Cell Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemoglobin SC Disease Hemoglobinopathies Sickle Cell Hemoglobin C Sickle Cell-beta-thalassemia Sickle-Cell; Hemoglobin Disease, Thalassemia Thalassemia

Age range

6 month–17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Dr Angela E Rankine- Mullings, Kingston, Jamaica

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Male or female aged from 6 months to 17.99 years of age (i.e. to the day before 18th birthday).
  • Diagnosis of sickle cell anemia (HbSS and HbSβº).
  • Parent(s)/legal guardian able and willing to provide written informed consent for the child to take part in the study.
  • Where applicable, the child should assent to undergo blood sampling for pharmacokinetic and biochemistry purposes and to allow physiological measurements to be made.

Exclusion criteria

  • Any clinically significant medical condition or abnormality, which, in the opinion of the Investigator, might have compromised the safety of the patient or which might have interfered with the study.
  • Hydroxyurea use within 6 months before enrolment.
  • Renal insufficiency (known creatinine more than twice the upper limit of normal (ULN) for age and >1.0 mg/dL [88.4 μmol/L]).
  • Clinical evidence of hepatic compromise with alanine aminotransferase (ALT) >3 times the ULN (a temporary swing in ALT did not result in exclusion).
  • Other significant organ system dysfunction based on the site Investigators discretion.
  • Severe active infections: fungal, viral or bacterial (as confirmed by culture), examples included tuberculosis, malaria, active hepatitis, osteomyelitis or any other illness that would have precluded the use of HU in normal clinical practice.
  • Active chronic leg ulcers.
  • Known allergy to oral HU solution or any of the excipients.
  • Positive pregnancy test for females of child-bearing potential (in post-menarcheal females) before initiation of treatment, unless participant was sexually abstinent. Note: True abstinence was considered as being in line with the preferred and usual lifestyle of the participant. Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • Inadequate contraception measures in sexually active females (post-menarcheal females) and males of child-bearing age (see Section 9.5.1.10.4).
  • Breastfeeding at study initiation.
  • Participation in another clinical trial of an IMP.
  • Known infection with HIV.

Treatment and study plan

Oral Hydroxyurea (100 mg/mL) Solution

Drug

Participants received Oral Hydroxyurea 15 mg/kg once daily. Escalated by 5 mg/kg/day every 8-12 weeks until maximum tolerated dose achieved, up to a maximum 35 mg/kg/day.

Primary outcomes

  1. Clearance (CL/F)

    Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

    Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).

  2. Volume of Distribution (V/F)

    Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

    Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).

  3. Time to Maximum Concentration (Tmax)

    Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

    Mean Tmax (h) pharmacokinetic parameter derived using the final population PK model.

  4. Maximum Plasma Concentration Cmax (ug/mL)

    Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

    Mean Cmax (ug/mL) pharmacokinetic parameter derived using the final population PK model.

  5. Area Under Plasma Concentration Time Curve (AUC 0-Inf)

    Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

    Mean AUC 0-Infinity (hr*ug/mL) pharmacokinetic parameters derived using the final population PK model.

  6. Terminal Half-life (Hours)

    Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

    Mean Terminal Half-life (hours) pharmacokinetic parameter derived using the final population PK model.

Secondary outcomes

  1. Adverse Events

    Time frame: Screening Up to Week 64

    Incidence of Adverse events during the course of the trial from screening to final follow up phone call at Week 64.

    Relatedness refers to 'at least possibly related to the IMP', with severity/toxicity assessed using the CTCAE Toxicity Grade and seriousness based on the standard definition for SAE in accordance with GCP. With the exception of SCA related events, requiring >7day hospitalisation, or extension of hospitalisation before being reported as an SAE due to their frequency within the disease population. All other non-SCA related SAEs were reportable.

  2. Absolute Neutrophil Count (ANC)

    Time frame: Baseline and Week 60 (or final visit); max 15 months on treatment

    Safety review for haematological toxicity (mild myelosuppression target: 1-3x10^9/L)

  3. White Blood Cell Count (Leukocytes)

    Time frame: Baseline to Week 60 or Final Visit; max 15 months on treatment

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  4. Platelets

    Time frame: Baseline to Week 60 (or Final Visit), max 15 months on treatment

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  5. Mean Corpuscular Hemoglobin (MCH)

    Time frame: Baseline to Week 60 (or Final Visit), max 15 months on treatment

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  6. Hematocrit

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  7. Bilirubin

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  8. Elevation in Liver Function Tests (LFTs)

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry, including Liver Function Tests (LFTs): Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Aspartate Amino Transferase (AST), Alanine Aminotransferase (ALT)

  9. Hemoglobin

    Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment

    Safety and efficacy of hydroxyurea therapy

  10. Bacterial Infections

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  11. Viral Infections

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  12. Fungal Infections

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  13. Leg Ulcers

    Time frame: Up to Week 60

    Impact of Hydroxyurea on Safety, Hematology and Biochemistry

  14. Fetal Hemoglobin

    Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment

    Biomarker endpoints of Hydroxyurea efficacy

  15. Mean Corpuscular Volume (MCV)

    Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment

    Biomarker endpoints of Hydroxyurea efficacy

  16. Cystatin C

    Time frame: PK1 (day 1), week 20-32 (6 months) and Week 60 (Final Visit)

    Biomarker Endpoints

  17. Incidence of Acute Vaso-Occlusive Pain Crises (VOC)

    Time frame: 12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP

    Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for vaso-occlusive crisis (Mean [SD])

  18. Number and Frequency of Blood Transfusions

    Time frame: Up to Week 60

    Clinical status endpoints, related to blood transfusions for treatment of SCA, this may be hospitalization, A&E, or in-clinic treatment from safety population (n=32)

  19. Acute Chest Syndrome (ACS)

    Time frame: 12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP

    Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for Acute Chest Syndrome (Mean [SD])

  20. Hospitalizations

    Time frame: 12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP

    Clinical Status endpoints, all hospitalisations (not ER/Accident without hospitalization) (Mean [SD])

  21. Dose Escalation i.e. Maximum Tolerated Dose (MTD)

    Time frame: Screening Up to Final Visit (Week 60 or Withdrawal), maximum 15 months on IMP

    Summary of maximum tolerated dose achieved in mg/kg (Mean [SD])

  22. Other SCA-related Hospitalizations

    Time frame: 12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP

    Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other Non-SCA related) (mean [SD])

  23. Parent/Caregiver Palatability and Acceptability Questionnaire

    Time frame: Taken once at any point after 8 weeks on study medication (or at early Withdrawal)

    Clinical status endpoints. Visual Analogue scale used to determine, taste, smell, aftertaste, acceptability and ease of dosing (1-100mm scale) with 1 being worst possible and 100 being best possible.

    Assessed for <6 years of age by parents/guardians. Assessed for >6 years of age, combination of parent/guardian and participant responses.

  24. Vitamin D

    Time frame: From Screening Up to Final Visit (Week 60 or WD)

    Biochemistry

  25. Other Non-SCA-related Hospitalizations

    Time frame: 12 months prior to treatment and 12 months post-treatment; maximum 15 months on IMP

    Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other SCA-related)

Other outcomes

  1. Transcranial Doppler Velocity

    Time frame: Baseline to Week 40-56 (Follow up scan).

    Exploratory Endpoint; clinical output of hydroxyurea treatment

Sponsors and collaborators

Lead sponsor

Nova Laboratories Limited

Industry

Registry information

Official study title

A Prospective Open Label, Pharmacokinetic Study of an Oral Hydroxyurea Solution in Children With Sickle Cell Anemia.

Acronym: HUPK

Important dates

Study start
2019
Primary completion
2021
Study completion
2021
First posted
Dec 4, 2018
Registry last updated
Oct 28, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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